Mapping RANKL- and OPG-expressing cells in bone tissue: the bone surface cells as activators of osteoclastogenesis and promoters of the denosumab rebound effect

兰克尔 德诺苏马布 骨吸收 化学 内科学 内分泌学 甲状旁腺激素 破骨细胞 骨重建 骨细胞 细胞生物学 骨质疏松症 医学 受体 激活剂(遗传学) 生物
作者
Bilal Mohamad El-Masri,Christina Møller Andreasen,Kaja Søndergaard Laursen,Viktoria B. Kofod,Xenia G. Borggaard,Malene H. Nielsen,Jesper Skovhus Thomsen,Annemarie Brüel,Mads Sølvsten Sørensen,Lars Juul Hansen,Albert Kim,Victoria E. Taylor,Caitlyn Massarotti,Michelle M. McDonald,Xiaomeng You,Julia F. Charles,Jean‐Marie Delaissé,Thomas Levin Andersen
出处
期刊:Bone research [Springer Nature]
卷期号:12 (1)
标识
DOI:10.1038/s41413-024-00362-4
摘要

Abstract Denosumab is a monoclonal anti-RANKL antibody that inhibits bone resorption, increases bone mass, and reduces fracture risk. Denosumab discontinuation causes an extensive wave of rebound resorption, but the cellular mechanisms remain poorly characterized. We utilized in situ hybridization (ISH) as a direct approach to identify the cells that activate osteoclastogenesis through the RANKL/OPG pathway. ISH was performed across species, skeletal sites, and following recombinant OPG (OPG:Fc) and parathyroid hormone 1–34 (PTH) treatment of mice. OPG:Fc treatment in mice induced an increased expression of RANKL mRNA mainly in trabecular, but not endocortical bone surface cells. Additionally, a decreased expression of OPG mRNA was detected in bone surface cells and osteocytes of both compartments. A similar but more pronounced effect on RANKL and OPG expression was seen one hour after PTH treatment. These findings suggest that bone surface cells and osteocytes conjointly regulate the activation of osteoclastogenesis, and that OPG:Fc treatment induces a local accumulation of osteoclastogenic activation sites, ready to recruit and activate osteoclasts upon treatment discontinuation. Analysis of publicly available single-cell RNA sequencing (scRNAseq) data from murine bone marrow stromal cells revealed that Tnfsf11 + cells expressed high levels of Mmp13 , Limch1 , and Wif1 , confirming their osteoprogenitor status. ISH confirmed co-expression of Mmp13 and Tnfsf11 in bone surface cells of both vehicle- and OPG:Fc-treated mice. Under physiological conditions of human/mouse bone, RANKL is expressed mainly by osteoprogenitors proximate to the osteoclasts, while OPG is expressed mainly by osteocytes and bone-forming osteoblasts.
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